Background: Warfarin, which requires coagulation monitoring, is associated with relatively high rates of thromboembolism despite providing adequate prophylaxis. This study compared an oral direct thrombin inhibitor, ximelagatran, with warfarin in order to evaluate the safety and efficacy of the medication for the prevention of venous thromboembolism in patients undergoing total knee arthroplasty.
Methods: Following surgery, patients were randomly assigned to fixed-dose oral ximelagatran (36 mg twice daily) or warfarin (target international normalized ratio, 2.5), both administered for seven to twelve days in a double-blind, double-dummy design. Warfarin was initiated on the evening of the day of surgery, and ximelagatran, on the morning after surgery. The primary efficacy end point was the incidence of asymptomatic deep-vein thrombosis determined by bilateral venography, objectively confirmed symptomatic deep-vein thrombosis or pulmonary embolism, and death from all causes during treatment.
Results: Adequate venograms or confirmed symptomatic events (efficacy population) were obtained for 1949 patients. Venous thromboembolism and death from all causes occurred in 22.5% (221) of 982 ximelagatran-treated patients and in 31.9% (308) of 967 warfarin-treated patients (p < 0.001). Proximal deep-vein thrombosis and pulmonary embolism were observed in 3.1% (thirty) and 0.2%, respectively, of the patients in the ximelagatran group and in 3.4% (thirty-three) and 0.4%, respectively, of the patients in the warfarin group. The six deaths from all causes included 0.3% (four) of the ximelagatran-treated patients and 0.2% (two) of the warfarin-treated patients. Major bleeding was noted in 1% (twelve) of the ximelagatran-treated patients and in 0.4% (five) of the warfarin-treated patients (p = 0.09).
Conclusions: Oral ximelagatran (36 mg twice daily), administered without coagulation monitoring or dose adjustment and started the day after total knee arthroplasty, demonstrates superior efficacy compared with warfarin prophylaxis, with no wound complications and no significant difference with respect to bleeding events, although the rate of major bleeding events was greater with ximelagatran than with warfarin.
Level of Evidence: Therapeutic Level I. See Instructions to Authors for a complete description of levels of evidence.
1 Orthopaedic Surgery, Scripps Clinic, 11025 North Torrey Pines Road, Suite 140, La Jolla, CA 92037. E-mail address: firstname.lastname@example.org
2 Clinical Development, AstraZeneca LP, 1800 Concord Pike, P.O. Box 15437, Wilmington, DE 19850-5437
3 Department of Orthopaedic Surgery, UCLA Medical Center, 10833 Leconte Avenue, CHS 76-134, Los Angeles, CA 90095
4 Veterans Administration Medical Center (151), 921 N.E. 13th Street, Oklahoma City, OK 73104
5 Department of Medicine, McMaster University, 1200 Main Street West, HSC-3W11, Hamilton, ON L8N 3Z5, Canada
6 UC Irvine at Mission, 27800-Medical Center Road, #126, Mission Viejo, CA 92691
7 Hematology/Oncology Unit, University of Rochester Medical Center, 601 Elmwood Avenue, Box 610, Rochester, NY 14642